1. Field of the Invention
The present invention relates to a novel method for producing nucleoside derivatives, more precisely to a novel method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-xcex2-D-threo-pentofuranosyl)adenine (hereinafter referred to as xe2x80x9cFddAxe2x80x9d) and its related compounds which are useful as anti-viral agents, to novel intermediates in the method, and to a novel method for producing the intermediates.
2. Description of the Related Art
It is reported that 9-(2,3-dideoxy-2-fluoro-xcex2-D-threo-pentofuranosyl)adenine (FddA) has a strong anti-viral activity against human immunodeficiency virus (HIV) and is greatly effective for treatment of acquired immune deficiency syndrome (AIDS) (see V. E. Marquetz, et al., Biochem. Pharmacol., (36) page 2719, 1987; P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987), and many clinical tests using it for the treatment of AIDS and AIDS-related complications (ARC) are being made at present. Recently, in addition, reported are FddA derivatives as modified at the nucleic acid base site to improve their potency (see C. K. Chu, et al., J.Med. Chem., (37), page 821, 1994; J. S. Driscoll, et al., J. Med. Chem., (39), page 1619, 1996; C. K. Chu, et al., J. Med. Chem., (39), page 4676, 1996).
The most direct method for producing FddA and its related compounds comprises substituting a substrate, of which the 3xe2x80x2-position in the saccharide moiety is deoxylated, at its 2xe2x80x2-position (see P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978, 1990; H. Shiragami, et al., Nucleosides and Nucleotides, (11), page 391, 1992). However, the yield in the conventional methods is extremely low or is not higher than 10% and the reagent, diethylaminosulfer trifuluoride (DAST), is not available in industrial amount, and therefore the methods could not be used for industrial production of FddA and its related compounds.
1. Problems to be Solved by the Invention
In the course of the completion to the present invention, the above and following problems in the related art have been also found by the present inventors.
Given the situation as above, it is desired to develop an inexpensive method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-xcex2-D-threo-pentofuranosyl)adenine (FddA) and its related compounds, in a simplified manner and at a high yield, in particular, an economical and industrial method for producing those nucleoside derivatives that comprises substituting a substrate, of which the 3xe2x80x2-position of the saccharide moiety is deoxylated, at its 2xe2x80x2-position at a high yield. Accordingly, the subject matter in the art is to provide such an excellent production method.
The object of the present invention is to develop an advantageous method for producing the nucleoside derivatives noted above, especially those having anti-viral activity, and to provide intermediates in the method and also a simple method for producing the intermediates.
We, the present inventors have assiduously studied in order to solve the problems noted above, and, as a result, have found, in a process for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-xcex2-D-threo-pentofuranosyl)adenine (FddA) and its related compounds, by subjecting a 3xe2x80x2-deoxy derivative of adenine to 2xe2x80x2-deoxylation/substitution with a flurine atom or the like (see P. herdewijn, et al., J. Med. Chem., (30), page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978, 1990; H. Shiragami, et al., Nucleosides and Nucleotides, (11), page 391, 1992 ), the yield thereof is extremely low mainly due to a rearrangement of adenine base.
It is reported that, by subjecting a derivative of adenine, of which the 3xe2x80x2-position is not deoxylated, to 2xe2x80x2-deoxylation/substitution with a fluorine atom or the like, the same kind of rearrangement has occurred as side reaction and lowered the yield (see K. A. Watanabe, et al., J. Org. Chem., (57), page 553, 1992 ). Furthermore, it is reported that, by chlorination at the 6-position of the nucleic acid, this kind of rearrangement can be suppressed (see T. Maruyama, et al., Chem. Pharm. Bull., (44), page 2331, 1996). However, it is not known the case of 3xe2x80x2-deoxy derivatives.
Therefore, we, the present inventors have produced novel intermediates of a general formula (1) mentioned below, which are derivatives as deoxylated at the 3xe2x80x2-position and substituted by a halogen atom at the 6-position of the nucleic acid. Using those novel intermediates, we have found that even substrates, of which the 3xe2x80x2-position of the nucleic acid is deoxylated, can suppress the troblesome rearrangement completely and can be substituted at the 2xe2x80x2-position at an extremely high yield. On the basis of these findings, we have completed the present invention.
Specifically, by subjecting a 3xe2x80x2-deoxy derivative of inosine to 6-halogenation step for halogenating it at the 6-position thereof to give a 6-halide of the derivative, and then subjecting it to 2xe2x80x2-deoxylation/substitution with a fluorine atom or the like, followed by further subjecting it to substitution with an amino group, a hydroxyl group or any other intended substituent at the 6-positioned halogen atom, we have made it possible to produce the intended nucleoside derivatives.
On the basis of our findings noted above, hereinunder illustrated is one embodiment of the production route to give nucleoside derivatives, which covers all the steps in series as concretely demonstrated in Examples to be mentioned hereinafter. All those steps and the compounds as produced therein are usable in the process of producing nucleoside derivatives of the present invention. Naturally, the invention encompasses not only all the steps constituting this production route but also any and every method comprising any one of those steps, novel intermediates as produced in those steps and even the use of those novel intermediates, especially the use thereof for producing various nucleoside derivatives. Production Route: 
In those formulae, W represents a halogen atom, X represents a halogen atom, Y represents a substituent of any of a fluorine atom, an azido group or a cyano group, Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a substituent of a formula OR4, a substituent of a formula SR4 and a substituent of a formula NHR4, R1 represents a protective group for the hydroxyl group, SO2R2represents a sulfonic acid-type leaving group, R3represents a protective group for the hydroxyl group, and R4 represents an optionally. phenyl-substituted, lower (e.g., C1-5) alkyl group.
Preferably, R2 represents a halogen atom, an optionally-substituted aryl, alkyl or aralkyl group, or an optionally-substituted alkylamino group.
Regarding the definitions and the meanings of the compounds of general formula (1) to (9) as referred to herein, it shall be understood that the compounds designated by the same formula number are the same ones even though they are not individually described herein.
The invention encompasses a novel method for producing the nucleoside derivatives mentioned herein from the novel intermediates (1) and also from various raw compounds, novel intermediates including the intermediates (1) which are for producing the nucleotide derivatives, a novel method for producing those intermediates, and the use of the intermediates. More precisely, the present invention encompasses the following matters.
(i) A method for producing a nucleoside derivative represented by the following general formula (8) or (9), comprising subjecting a 3xe2x80x2-deoxy derivative of inosine, of which a part or all of the two hydroxyl groups may or may not be optionally protected, to 6-halogenation step for halogenating the compound at the 6-position thereof to give a 6-halide of the derivative, and then subjecting it, optionally after protecting its 5xe2x80x2-position, to 2xe2x80x2-deoxylation/Y-substitution reaction step followed by further subjecting it to Z-substitution reaction at its 6-halogen atom: 
In the case of optionally protected 5xe2x80x2-position with a protective group in the derivative, the protective group may be de-protected in the suitable step, for example, before or after the Z-substitution reaction at its 6-halogen atom.
In such formula, as so mentioned hereinabove, Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group, Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a substituent of a formula OR4, a substituent of a formula SR4 and a substituent of a formula NHR4, R1 represents a protective group for the hydroxyl group, and R4 represents an optionally phenyl-substituted, lower (e.g., C1-5) alkyl group.
The compound (8) obtained herein may be optionally subjected to deprotection at the 5xe2x80x2-position to convert them into 5xe2x80x2-deprotected derivative (9), as will be mentioned after.
On the other hand, the obtained compound (8xe2x80x2) mentioned after may be optionally subjected to substitution with a group Z at its 6-halogen atom to give such derivative (9), as will be also mentioned after.
The nucleoside derivatives, compounds (9) in the present invention have anti-viral activity, in which Z is preferably a hydrogen atom, an amino group, a hydroxyl group, an azido group, a methylamino group, a methyloxy group or the like.
(ii) A method for producing a nucleoside derivative represented by the general formula (8) or (8xe2x80x2) noted above, which comprises subjecting a compound represented by the following general formula (1) to 2xe2x80x2-deoxylation/Y-substitution reaction to give a compound represented by the following general formula (3);
and then subjecting the resulting compound (3) to substitution with a group Z at its 6-halogen atom to give the compound (8),
or subjecting the compound (3) to deprotection at the 5xe2x80x2-position to convert the same into 5xe2x80x2-deprotected derivative (8xe2x80x2).
One embodiment of the method comprises a step of processing the compound of formula (3), especially preferably that in which X is a chlorine atom and Y is a fluorine atom, to thereby substitute the substituent X with an amino group, preferably processing it in a solution of ammonia in an alcohol (e.g., methanol, ethanol, propanol, etc.), or a step of processing the compound to thereby substitute the substituent X with a hydroxyl group, preferably processing it in an aqueous solution of an alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), or a step of processing the compound to thereby substitute the substituent X with a hydrogen atom, preferably processing it with hydrogen in the presence of a reduction catalyst (e.g., palladium-carbon, Raney nickel, etc.), or a step of processing the compound to thereby substitute the substituent X with an azido group, preferably processing it with an alkali metal azide (e.g., sodium azide, lithium azide, etc.), to thereby produceng the nucleoside derivative of formula (8), and optionally comprises a step of deprotecting the resulting derivative at the protective group R1 to obtain a nucleoside derivative represented by the following general formula (9).
Alternatively, the compound firstly (3) may be subjected to such above deprotecting step at the protective group R1 to give the derivative (8xe2x80x2), and then the obtained this derivative (8xe2x80x2) may be subjected to substitution with a group Z at its 6-halogen atom to give the compound (9) in the same manner as above. 
In those above formulae, as so mentioned hereinabove, X represents a halogen atom, Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group, z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a substituent of a formula OR4, a substituent of a formula SR4 and a substituent of a formula NHR4, R1 represents a protective group for the hydroxyl group, and R4 represents an optionally phenyl-substituted, lower (e.g., C1-5) alkyl group.
(iii) One embodiment of the method of (ii), wherein the reaction step includes a compound of the following formula (2) as the intermediate: 
In this formula, as so mentioned hereinabove, X represents a halogen atom, R1 represents a protective group for the hydroxyl group, and SO2R2 represents a sulfonic acid-type leaving group.
(iv) A method for producing compounds of formula (3) noted above, which comprise;
(a) subjecting a compound of formula (1) noted above to 2xe2x80x2-deoxylation/Y-substitution reaction step, preferably for removing the hydroxyl group from the compound followed by introducing a substituent Y, a fluorine atom, an azido group or a cyano group, thereinto, more preferably by reacting the compound with an alkylaminosulfur trifluoride reagent or a fluoroalkylamine reagent, or
(b) subjecting a compound of formula (2) noted above to removal of 2xe2x80x2-leaving group/Y-substitution reaction step, or that is, processing the compound to thereby remove its O-sulfonic acid-type leaving group therefrom and introduce a substitutent Y, a fluorine atom, an azido group or a cyano group, thereinto, preferably by reacting the compound with a reagent for attaining the substitution with a fluorine atom, an azido group or a cyano group, for example, reacting it with any one of azides, cyanides and fluorides, to thereby produce the intended compound (3).
In the meantime, the removal of 2xe2x80x2-leaving group in the present invention, the sulfonic acid-type leaving group is removed in the form of the O-sulfonic acid-type leaving group.
In these formulae, as so mentioned hereinabove, X represents a halogen atom, Y represents any one of a fluorine atom, an azido group and a cyano group, R1 represents a protective group for the hydroxyl group, and SO2R2 represents a sulfonic acid-type leaving group. Preferably, R2 represents a substituent of any one of a halogen atom, an aryl, alkyl and aralkyl group and also an alkylamino group, which may be optionally substituted (for example, with a halogen atom, etc.).
(v) Novel compounds of formulae (1) and (2) noted above, which are intermediates in the above-mentioned methods.
In those, X, Y, R1 and SO2R2 have the same meanings as defined above.
(vi) One embodiment of the method (iv), in which the compound of formula (2) is prepared by reacting a compound of formula (1) noted above with a reagent for inserting a sulfonic acid-type leaving group thereinto, preferably by reacting it with a sulfonyl halide or a sulfonic acid anhydride, or reacting it with sulfuryl chloride and then with an amine or a halogens such as a fluorine or the like.
(vii) One embodiment of the method (i) or (ii), which comprises at least one of the following steps (A) to (E):
(A): a step of forming a compound of formula (3) according to the step (a) or (b) in the method (iv) noted above,
(B): a step of dehalogenating a compound represented by the following general formula (7) to give a compound represented by the following general formula (4),
(C): a step of reacting a compound represented by the following general formula (6) with a reagent for selectively protecting the 5xe2x80x2-position of the compound to give a compound of formula (1) noted above,
(D): a step of subjecting a compound of formula (1) noted above to reaction of inserting a sulfonic acid-type leaving group thereinto, preferably by reacting the compound with a sulfonyl halide or a sulfonic acid anhydride, or reacting it with sulfuryl chloride and then with an amine or a halogen such as a fluorine or the like, to give a compound of the following general formula (2), and
(E): a step of selectively halogenating a compound of the following general formula (4) at its 6-position with a halogenating agent to give a compound represented by the following general formula (5). 
In those above formulae, as so mentioned hereinabove, X represents a halogen atom, Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group, R1 represents a protective group for the hydroxyl group, SO2R2 represents a sulfonic acid-type leaving group, in which R2 is preferably a substituent of any of a halogen atom, and an aryl, alkyl or aralkyl group which may be optionally substituted (for example, with a halogen atom, etc.), and an alkylamino group which may be optionally substituted (for example, with a halogen atom, etc.), and R3 represents a protective group for the hydroxyl group.
(viii) Novel compounds of formula (4) noted above, which are intermediates in the above-mentioned methods.
As so mentioned hereinabove, R3 represents a protective group for the hydroxyl group.
(ix) A method for producing intermediates, which comprises at least any one of the steps (B) to (E).
This method for producing intermediates is usable in the method (vii) noted above. Apart from this, the method is also applicable to the production of other various useful compounds, as being simple and easy. Anyhow, this method is an excellent method for producing various intermediates.
In those formulae, as so mentioned hereinabove, X represents a halogen atom, Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group, R1 represents a protective group for the hydroxyl group, SO2R2 represents a sulfonic acid-type leaving group, in which R2 is preferably a substituent of any one of a halogen atom, and an aryl, alkyl or aralkyl group which may be optionally substituted (for example, with a halogen atom, etc.), and also an alkylamino group which may be optionally substituted (for example, with a halogen atom, etc.), and R3 represents a protective group for the hydroxyl group.
(x) Another embodiment of the method (i) or (ii) for producing nucleoside derivatives of the above-mentioned compounds (8), (8xe2x80x2) or (9), in which is used any one in the intermediates covered in the (viii) noted above.
In this, as so mentioned hereinabove, X represents a halogen atom, Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group, R1 represents a protective group for the hydroxyl group, SO2R2 represents a sulfonic acid-type leaving group such as that mentioned above, in which R2 is preferably a substituent of any one of a halogen atom, and an aryl, alkyl or aralkyl group which may be optionally substituted (for example, with a halogen atom, etc.), and also an alkylamino group which may be optionally substituted (for example, with a halogen atom, etc.), and R3 represents a protective group for the hydroxyl group.
Modes of carrying out the invention are described below.
Compounds of formula (7) noted above, such as typically 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-xcex2-D-xylofuranosyl)adenine, which are used in the invention, can be produced with ease in accordance with known methods (for example, see J. G. Moffatt, et al., J. Am. Chem. Soc., (95), page 4025, 1973). The substituent W is a halogen atom such as bromine.
The hydroxyl-protecting group, R3 includes, for example, an acyl group (having from 1 to 10 carbon atoms), such as acetyl or benzoyl; an aralkyl group such as benzyl; and an alkyl group (having from 1 to 5 carbon atoms), such as allyl.
Compounds of formula (4) noted above for use in the invention can be obtained by de-halogenating the compounds of formula (7). To de-halogenate them, employable is any per-se known de-halogenating method, but preferred is a method of reducing the compound (7) with a radical reaction reagent, such as tri-n-butyl tin hydride, tris(trimethylsilyl)silane, diphenylsilane or diphenylmethylsilane in the presence of a radical reaction initiator such as azobisisobutyronitrile; or a method of reducing it with hydrogen in the presence of a reduction catalyst such as palladium-carbon or Raney nickel.
The compounds of formula (4) for use in the invention can also be obtained in any per-se known method (for example, a method for producing them from compounds of formula (7), such as that described by H. Shiragami et al., in Nucleosides and Nucleotides, (15), page 31, 1996). For example, 3xe2x80x2-deoxyinosine is prepared and any hydroxyl groups of the compound are protected to give the intended compound (4).
Compounds of formula (5) noted above for use in the invention have a halogen atom (e.g., chlorine) at the 6-position, and these are preferably obtained by halogenating a compound of formula (4) selectively at its 6-position with a halogenating agent. The halogenating agent includes, for example, a chlorinating agent of a combination of phosphorus oxychloride and N,N-dimethylaniline or a combination of sulfuryl chloride and dimethylformamide, and a chlorinating agent of dimethylchloromethyleneammonium chloride.
Compounds of formula (6) noted above for use in the invention can be obtained by de-protecting the compounds of formula (5). For the de-protection, preferably used is a mild method that may have no influence on the 6-halogen atom of the compounds (5). For example, compounds of formula (5) wherein X is a chlorine atom and R3 is an acyl group, can be easily de-protected with ammonia or sodium methoxide as dissolved in an alcohol, such as methanol, without being influenced at the chlorine atom.
Compounds of formulae (5) and (6) noted above for use in the invention may be produced in per-se known methods (for example, see C. K. Chu et al., WO-9709052 (1997); Frederick William Hurry et al., Japanese Patent Kokoku Publication JP-B-42-17903), or that is, by coupling the nucleic acid base moiety and the saccharide moiety. In general, however, the known methods produce mixtures with unnecessary xcex1-anomers, and therefore indispensably require the separation of the intended products from the mixtures. In addition, the yield of the intended products to be produced in the known methods is low. Therefore, the method of the invention that uses compounds (4) is preferred, as being easy and economical in industrial production of the compounds (5) and (6). The invention encompasses those compounds (4).
Compounds of formula (1) noted above, which the invention encompasses, can be produced by reacting the compound of formula (6) with a reagent capable of selectively protecting the 5xe2x80x2-position of the nucleosides.
In formula (1), R1 is a protective group for the hydroxyl group, which may or may not be substituted (for example, with a halogen atom, an alkyl group having from 1 to 5 carbon atoms, an alkyloxy group having from 1 to 5 carbon atoms, etc.), and the protective group includes, for example, an acyl group such as acetyl or benzoyl; an alkyl group such as methoxymethyl or allyl; an aralkyl group such as benzyl or triphenylmethyl; a silyl group such as trimethylsilyl. As the reagent that gives such a protective group, for example, preferably used is any of an acylating agent, an alkylating agent, an aralkylating agent and an organic silylating agent. The acylating agent includes, for example, acid anhydrides such as acetic anhydride and benzoic anhydride, and acid halides such as acyl chloride and benzoyl chloride.
The alkylating agent includes, for example, alkyl halides such as chloromethyl methyl ether and allyl bromide. The aralkylating agent includes, for example, aralkyl halides such as benzyl bromide and triphenylmethyl chloride. The organic silylating agent includes, for example, organic silyl halides such as trimethylsilyl chloride. The reaction of the compound (6) with the protecting reagent is preferably effected in the presence of a base. The base usable in the reaction includes, for example, hydroxylamine, ammonia and their salts; primary to quaternary amines and their salts; metal hydroxides such as barium hydroxide; metal alkoxides such as sodium methoxide and potassium methoxide; lithium-ammonia solution; ion exchange resins; carbonates such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate; phosphates such as disodium phosphate; acetates such as sodium acetate; and alkaline solutions of sodium hydroxide, lithium hydroxide or the like.
Regarding the reaction condition, the two may be reacted in a suitable solvent. As the solvent, preferably used is an organic solvent such as ethyl acetate, toluene, methylene chloride or methanol. The reaction solvent may be or may not be dewatered. Anyhow, after the reaction, the base, if used, in the reaction mixture is optionally neutralized, and the product formed can be isolated from the mixture through ordinary extraction using an organic solvent such as ethyl acetate, toluene or methylene chloride. Apart from this, the reaction mixture may be directly subjected to the next step without isolating the product therefrom.
Compounds of formula (1) wherein R3 and R1 are the same, for example, R3=R1=acetyl or benzoyl, may be obtained by de-protecting the compound of formula (5) selectively at the 2xe2x80x2-protective group.
Of compounds of formula (2) noted above, the hydrogen atom in the 2xe2x80x2-hydroxyl group is substituted with a sulfonic acid-type leaving group (SO2R2). In those, R2 is preferably a substituent of any one of a halogen atom, and an aryl (having from 6 to 10 carbon atoms, such as phenyl), alkyl (having from 1 to 5 carbon atoms) or aralkyl (having from 7 to 19 carbon atoms, such as benzyl) group, which may or may not be substituted (for example, with a halogen atom, an alkyl group having from 1 to 5 carbon atoms, a nitro group, an alkyloxy group of which the alkyl moiety has from 1 to 5 carbon atoms, and the like), and also an alkylamino group (having from 1 to 6 carbon atoms), which may or may not be substituted (for example, with a halogen atom, an alkyl group having from 1 to 5 carbon atoms, a nitro group, an alkyloxy group of which the alkyl moiety has from 1 to 5 carbon atoms, and the like). More preferably, the protective group is any one of a chlorosulfonyl group, a fluorosulfonyl group, an imidazolesulfonyl group, a trifluoromethanesulfonyl group, a methanesulfonyl group, a an arylsulfonyl group such as a paratoluenesulfonyl, paranitrobenzenesulfonyl and benzenesulfonyl group, and the like.
Those compounds of formula (2) can be obtained by reacting the compound of formula (1) with a sulfonyl halide or a sulfonic acid anhydride, or by reacting it with sulfuryl chloride and then with an amine or a halogen. The sulfonyl halide includes, for example, arylsulfonyl halides such as paratoluenesulfonyl chloride and paranitrobenzenesulfonyl chloride; alkylsulfonyl halides such as methanesulfonyl chloride; aralkylsulfonyl halides such as benzylsulfonyl chloride; and halogenoalkylsulfonyl halides such as trifluoromethanesulfonyl chloride. The sulfonic acid anhydride includes, for example, arylsulfonic acid anhydrides such as paratoluenesulfonic acid anhydride and paranitrobenzenesulfonic acid anhydride; alkylsulfonic acid anhydrides such as methanesulfonic acid anhydride; aralkylsulfonic acid anhydrides such as benzylsulfonic acid anhydride; and halogenoalkylsulfonic acid anhydrides such as trifluoromethanesulfonic acid anhydride. The amine includes, for example, imidazole. The halogen includes, for example, fluorine.
The reaction to give compounds (2) may be effected in a suitable solvent. For this, preferably used is an organic solvent such as ethyl acetate, toluene or methylene chloride. The reaction may be effected in the presence of a basic catalyst such as pyridine, dimethylaminopyridine, triethylamine or the like. After the reaction, the basic catalyst, if used, in the reaction mixture is optionally neutralized, and the product formed can be isolated from the mixture through ordinary extraction using an organic solvent such as ethyl acetate, toluene and methylene chloride, And the like. Apart from this, the reaction mixture may be directly subjected to the next step without isolating the product therefrom.
In compounds of formula (3) noted above for use in the invention, Y is any one of a fluorine atom, an azido group and a cyano group. Those compounds (3) can be obtained by reacting the compound of formula (2) preferably with an azide, a cyanide or a fluoride. The azide includes, for example, alkali metal azides such as sodium azide and lithium azide; as well as ammonium azide and trimethylsilyl azide. The cyanide includes, for example, alkali metal cyanides such as sodium cyanide and lithium cyanide. The fluoride includes, for example, hydrogen fluoride; alkali metal fluorides such as lithium fluoride, potassium fluoride and cesium fluoride; alkylammonium fluorides such as tetrabutylammonium fluoride, pyridinium polyhydrogenfluoride and triethylamine trihydrofluoride; alkylaminosulfur trifluorides such as diethylaminosulfur trifluoride and morpholinosulfur trifluoride; and fluoroalkylamines such as Yarovenko reagent and Ishikawa reagent.
The reaction to give compounds (3) may be effected in a suitable solvent. For this, preferably used is an organic solvent such as ethyl acetate, toluene or methylene chloride. The reaction may be effected in the presence of a basic catalyst such as pyridine, dimethylaminopyridine or triethylamine. After the reaction, the basic catalyst, if used, in the reaction mixture is optionally neutralized, and the product formed can be isolated from the mixture through ordinary extraction using an organic solvent such as ethyl acetate, toluene or methylene chloride.
Compounds of formula (3) noted above for use in the invention, wherein Y is a fluorine atom, can be obtained by reacting the compound of formula (1) with a fluoride. The fluoride for this includes, for example, alkylaminosulfur trifluorides such as diethylaminosulfur trifluoride and morpholinosulfur trifluoride. This reaction may be effected in a suitable solvent. For this, preferably used is an organic solvent such as ethyl acetate, toluene and methylene chloride. The reaction may be effected in the presence of a basic catalyst such as pyridine, dimethylaminopyridine and triethylamine.
Compounds of formula (3) noted above for use in the invention, wherein X is a chlorine atom and Y is a fluorine atom, may be processed with ammonia as dissolved in methanol under pressure to thereby substitute X with an amino group, and thereafter the protective group R1 in the resulting compounds may be de-protected in any suitable manner to give FddA. However, the usefulness of the compounds illustrated herein is not limited to this case.
To produce nucleoside derivatives of formula (8) noted above, for example, the compounds of formula (3) may be subjected to any of the following reaction steps.
To obtain the derivatives (8) wherein Z is an amino group, the compound (3) is processed with ammonia as dissolved in an alcohol such as methanol under pressure.
To obtain the derivatives (8) wherein Z is a hydroxyl group, the compound (3) is processed with an aqueous solution of an alkali hydroxide such as sodium hydroxide and potassium hydroxide.
To obtain the derivatives (8) wherein Z is a hydrogen atom, the compound (3) is processed with hydrogen in the presence of a reduction catalyst such as palladium-carbon.
To obtain the derivatives (8) wherein Z is an azido group, the compound (3) is processed with an alkali metal azide, such as sodium azide or lithium azide, in a solvent capable of dissolving the metal azide, such as dimethylformamide.
To obtain the derivatives (8) wherein Z is OR4 or SR4, the compound (3) is processed with a corresponding alkyl alcohol or alkyl thiol having been activated with an alkali metal halide such as a sodium halide.
To obtain the derivatives (8) wherein Z is NHR4, the compound (3) is processed with an alkylamine (corresponding to the intended substituent, such as methylamine), preferably in an inert solvent such as dimethylformamide.
In formula (8), R4 indicates an optionally phenyl-substituted lower (C1-5) alkyl group, such as a methyl, ethyl, propyl, butyl and benzyl group.
Nucleoside derivatives of formula (9) may be produced with ease by de-protecting the compounds of formula (8). For example, compounds (8) wherein R1 is an acyl group such as an acetyl and benzoyl group may be processed with an alkali (e.g., sodium hydroxide, potassium hydroxide); those wherein R1 is an alkyl group such as a methoxymethyl and allyl group may be processed with an acid such as hydrochloric acid and acetic acid; those wherein R1 is an aralkyl group such as a benzyl or triphenylmethyl group may be processed with hydrogen in the presence of a reduction catalyst such as palladium-carbon and Raney nickel, or may be processed with an acid such as acetic acid; and those wherein R1 is a silyl group such as a trimethylsilyl group may be processed with tetraammonium fluoride or the like, to thereby give the derivatives of formula (9).
Alternatively, the above mentioned de-protecting reaction step at the 5xe2x80x2-potion thereof may be conducted and then substitution reaction with Z group may be conducted. In this case,the compound (3) firstly may be subjected to such above deprotecting step at the protective group R1 in the same manner as above to give the derivative (8xe2x80x2), and then thus obtained derivative (8xe2x80x2) may be subjected to substitution with a group Z at its 6-halogen atom to give the compound (9) also in the same manner as above.